The OBR Blog

More than 30,000 attendees from all over the world are expected at the 2013 Annual Meeting of ASCO, the “Mercedes Benz” of cancer meetings in the United States. Seven of the more than 4,700 abstracts to be presented were featured at the official pre-meeting Presscast on May 15, 2013.

The featured abstracts can be categorized as follows:

3 studies showed that “less is more” in cancer treatment;

2 studies focused on promising results with novel immunotherapies in melanoma and other cancers;

1 study featured Phase I results with the first-in-class PI3delta kinase inhibitor in the treatment of chronic lymphocytic leukemia (CLL); and

Stakeholders involved in fine-tuning resource utilization will be interested in a study showing that standard low-dose radiation is superior to high-dose radiation in the treatment of non-small cell lung cancer (NSCLC); that surveillance alone is a valid strategy for patients with stage I seminoma following primary treatment with orchiectomy; and that most relapses of diffuse large B-cell lymphoma (DLBCL) are picked up by physical exam or lab test abnormalities rather than by routine imaging.

While earlier studies suggested that higher doses of radiation could provide better local control, this study clearly demonstrates that it is associated with much shorter survival, said Jeffrey D. Bradley, MD, Washington University School of Medicine in St. Louis, MO. “The biological reasons for failure of the high dose with respect to overall survival and local-regional control are not readily apparent,” he said.

A long-term study of 1,822 patients suggests that adjuvant chemotherapy and radiation can be avoided in men with stage I seminoma, and surveillance is sufficient follow-up after surgery.

In the study, 99.6% of men followed by a 5-year surveillance program were alive 10 years after diagnosis. In the study, 19.5% of patients had a relapse, which was treated with radiotherapy, chemotherapy, or surgery.

“This means that for every 1,000 men followed on a surveillance program, only 4 die within 10 years,” said Mette Sakso Mortensen, MD, Copenhagen University, Denmark.

A separate study showed that routine use of CT or PET scans did not improve detection of relapse in patients with DLBCL. The vast majority of relapses were identified by abnormal physical exams, laboratory test findings, and/or development of symptoms.

At about 5 years of follow-up after initial treatment, the relapse rate was 20%. At the time of relapse, 68% of patients were symptomatic, 42% had an abnormal physical exam, and 55% had abnormal blood tests. Planned surveillance scans detected relapses in only 8 out of 537 patients (1.5%) with no symptoms before relapse.

Lead author Carrie A. Thompson, MD, Dana-Farber Cancer Institute in Boston said that patients should be vigilant about reporting symptoms between scheduled visits.

Two preliminary Phase 1 studies showed that using an anti-PD-L1 targeted antibody to unlock “brakes” that prevent T-cells from attacking tumor cells is a strategy worth pursuing in melanoma and other advanced cancers.

The first study evaluated MPDL3280A (Genentech), an anti-PD-L1 antibody, in 140 patients with advanced lung, melanoma, kidney, and gastric cancers that had progressed on previous treatments. The study found that the drug was safe and achieved robust tumor shrinkage, with the best results seen in lung cancer and melanoma. The study has expanded to 275 patients. Further study is needed, and Phase 2 and 3 studies are planned. Ultimately, the drug will probably be combined with other anti-cancer therapies, including immunotherapy and targeted therapy, said Roy S. Herbst, MD, PhD, Yale Cancer Center, New Haven, CT.

A separate Phase 1 study evaluated the combination of ipilimumab and the anti PD-L1 antibody nivolumab (Bristol Myers Squibb) in 37 patients with inoperable stage III and IV melanoma, with highly encouraging responses, even in patients who did not previously respond to ipilimumab. Side effects were manageable in this trial, and a randomized Phase 3 trial of the combination as first-line therapy for advanced melanoma will be mounted soon. Lead author was Jedd D. Wolchok, MD, PhD, Memorial Sloan-Kettering Cancer Center, New York City.

PI3K Inhibitor

A Phase 1 study in 54 patients with treatment-resistant CLL showed that the first-in-class PI3K inhibitor idelalisib (Gilead Sciences) was effective in delaying the time to progression by about 17 months. This is better than what would be expected in a sixth-line therapy, which might usually delay time to progression by about 6 to 12 months, said Jennifer Brown, MD, PhD, Dana-Farber Cancer Institute. Side effects were manageable.

Investigators were enthusiastic about both anti-PD-L1 antibodies and the novel PI13K inhibitor. If further study confirms the benefit of idelalisib, it will join ibrutinib as a potential advance in treating CLL; ibrutinib is a Bruton’s Tyrosine Kinase inhibitor that has had encouraging Phase II results in CLL and is now in Phase 3 development.

Fitness and Cancer Outcomes

Several studies have shown that physical exercise has beneficial effects in preventing recurrence of several types of cancer. A new study looks at a different measure of physical status – physical fitness, which can be objectively quantitated on maximal exercise tolerance testing by units of fitness called metabolic equivalents (METS).

For the first time, a study has shown that being physically fit reduces the odds of developing lung and colorectal cancer, and the odds of dying of lung, colorectal, and prostate cancer. “This is the first study to explore fitness as a marker of future cancer risk prognosis,” said lead author Susan Lakoski, MD, University of Vermont in Burlington.

The study, based on Medicare claims data, included 17,049 men who had a single cardiovascular fitness assessment at a mean age of 50 years as part of a preventive health program offered at the Cooper Institute in Dallas, TX.

In men in the highest quintile of physical fitness, the risk of being diagnosed with lung cancer or colorectal cancer was reduced by 68% and 38%, respectively, compared with men in the lowest quintile of physical fitness. Fitness level had no impact on risk of developing prostate cancer.

However, among men who developed lung, colorectal, or prostate cancer, those at a higher level of fitness in their 50s had a lower risk of dying of any of these cancers, as well as of cardiovascular disease. As small as a 1 MET improvement in fitness reduced the risk of cancer-related death by 14% and the risk of death related to cardiovascular disease by 23%.

Another important finding was that low levels of physical fitness were associated with an increased risk of cancer and cardiovascular disease even in non-obese men, suggesting that patients should improve their levels of physical fitness regardless of body weight.

The annual meeting of the American Society of Clinical Oncology (ASCO) is just around the corner, and Kantar Health is excited to preview the top abstracts. The 2013 meeting promises to be packed with the latest data and trends from the world of oncology, but it may not have an overwhelming number of practice-changing, blockbuster presentations compared with conferences in the recent past. The following is a brief synopsis of the three abstracts that are likely to generate the most discussion and have the highest impact. For a full discussion of all 10 of our top abstracts, please see the associated article in the May issue of OBR Green.

Avastin in Newly Diagnosed Glioblastoma

Avastin® (bevacizumab, Roche/Genentech) was granted accelerated FDA approval in 2009 for the treatment of relapsed glioblastoma (GBM). In November 2012, results for the Phase III AVAglio trial showed that adding Avastin to chemoradiotherapy for the treatment of newly diagnosed GBM patients improved progression-free survival (PFS), but the interim overall survival (OS) results did not reach statistical significance. Presented at ASCO this year will be the results from the RTOG 0825 trial that has a nearly identical trial design as AVAglio. This plenary presentation could serve to provide a more convincing narrative for the use of Avastin in the newly diagnosed GBM setting.

Physicians are becoming familiar with Avastin showing a PFS benefit but not significantly affecting OS. This may give some physicians pause after the AVAglio results followed this same pattern. Will the RTOG 0825 trial change that perception, or will we see a similar pattern of PFS without OS? The availability and high use of Avastin in relapsed GBM may certainly confound the OS results from these studies, so it will be interesting to see whether there is any trend in the data. Given the high unmet need in GBM and the complete lack of active agents beyond temozolomide, the PFS benefit could be enough to maintain Avastin as a new option in newly diagnosed patients, but lacking OS could hinder its ability to become the new standard of care. Presentations: RTOG 0825, Abstract 1, Sunday, June 2, 1:50 PM; AVAglio, Abstract 2005, Saturday, June 1, 4:30 PM

FIRE-3: We’re “Burning” to Finally See a Head-to-Head of Avastin versus Erbitux in Colorectal Cancer

In KRAS wild type colorectal cancer (CRC), Avastin is currently the first-line standard of care in combination with chemotherapy in the United States, but European physicians are utilizing about equal amounts of Erbitux compared with Avastin, according to Kantar Health’s most recent CancerMPact® Treatment Architecture data. Both targeted agents significantly improve PFS compared with chemotherapy alone, and both have demonstrated a strong trend to OS benefit in recent studies. In the absence of comparative data between the two agents, the current practice has evolved based on safety profile, cost of therapy and order of market entry. In the United States, the Cancer and Leukemia Group B (CALGB) sponsored the Phase III 80405 study, and in Europe a German academic group initiated the FIRE-3 study, both comparing first-line chemotherapy in combination with Avastin or Erbitux in KRAS wild type patients. FIRE-3 will be the first to report at ASCO 2013.

Several aspects of the data will be key to evaluate. PFS and OS will take top billing, but other endpoints such as response rate, resectability of liver metastases, safety and its impact on dose intensity will also influence treatment patterns. European physicians are more likely to be influenced by the FIRE-3 results, given that the treatment arms closely resemble the treatment standards in Europe. The impact on the U.S. market may be lower, since U.S. physicians typically use FOLFOX in the first line in combination with Avastin, so they may not see the FIRE-3 study as accurately depicting their first-line treatment of choice, as chemotherapy is limited to FOLFIRI in that study. The FIRE-3 results could raise some serious questions if Erbitux can show superiority versus Avastin on any of the efficacy endpoints. Presentation: FIRE-3, Abstract LBA3506, Saturday, June 1, 4:45 PM

As a CD20 antibody, obinutuzumab (also known as GA101, Roche/Genentech) draws frequent comparisons to Rituxan® (rituximab, Roche/Genentech), but Roche hopes the unique epitope and glycosylation of obinutuzumab will sufficiently distinguish it from Rituxan and ultimately prove superior.

The presentation at ASCO 2013 will detail the efficacy results from the first stage of the Phase III CLL11 trial comparing obinutuzumab plus chlorambucil versus chlorambucil alone. In January 2013, Roche announced via press release that obinutuzumab plus chlorambucil significantly reduced the risk of disease worsening or death compared with chlorambucil alone, and the study met the planned requirements of the futility analysis allowing its continuation. Additionally in that release, the company stated their plans to file for regulatory approval based on the results of this phase of the study.

It is not entirely surprising that the combination of obinutuzumab plus chlorambucil showed superiority versus chlorambucil monotherapy, but it will be the results versus Rituxan plus chlorambucil that will really generate some buzz if obinutuzumab is able to out-duel Rituxan in terms of efficacy. The oncology community will likely have to wait another year for that data, but the ASCO presentation should give an idea of the magnitude of benefit achieved by adding obinutuzumab to chlorambucil, which could hint at probabilities for success in the second stage of the trial. Presentation: CLL11, Abstract 7004, Tuesday, June 4, 9:15 AM

In addition to the abstracts above, the full article discusses the key abstracts listed in the table below.

Investors in shares of AVEO found out last week that the FDA is not waving through every oncology drug that comes down the road. The vote by the Oncologic Drugs Advisory Committee (ODAC), which we recently previewed in this column, was a resounding 13-1 against a recommendation for approval for AVEO’s multi-VEGF kinase inhibitor, tivozanib. As you can read, we expected the panel discussion to be a difficult one that would result in a narrow victory for tivozanib. Our discussion with Dr. Brian Rini of the Cleveland Clinic, the principal investigator of the AXIS study for axitinib, the most recent VEGF kinase inhibitor to gain a positive ODAC vote and FDA approval, felt that AVEO would overcome the trial’s obvious flaws (discussed below), was even more positive than even our measured assessment. As we wrote, Dr. Rini felt that, while concerning, the inverted OS curve could be explained by the trial’s one-way crossover, and that the company would prevail.

Obviously, FDA and all the panel members save one didn’t see it that way. In fact, it appears that the meeting was over before it even started. While we have seen drug sponsors overcome negative briefing documents and even hostile assessments from medical reviewers, it was clear from the opening comments by Amna Ibrahim of the Division of Oncology Products that there was no way AVEO was coming away from the meeting with a positive recommendation. Comments from cancer czar, Dr. Richard Pazdur, Director of the Office of Hematology and Oncology Products, sealed the company’s fate late in the afternoon with his dubious perspective on the drug’s risk/benefit relationship.

A number of issues doomed tivozanib’s prospects but clearly the inverted OS curve was something the drug could not surmount. Our concerns were raise when the briefing documents were made available and the FDA review narrative indicated that the FDA requested in May of 2012 that AVEO conduct another study of tivozanib in a patient population “comparable to that in the US” (recall that the vast majority of patients in the TIVO-1 trial were from Eastern Europe). Whether AVEO refused or declined to follow the FDA’s recommendation, investors still don’t know. One thing is certain, however; the regulatory track record of sponsors who decline to follow what the FDA recommends and instead throw themselves on the mercy of an advisory committee is poor. Additionally, the multitude of therapeutic options clearly has raised the bar, formally or informally, for follow-on compounds with mechanisms similar to those already on the market. Surprisingly, the lengthy absolute level of OS in the tivozanib arm and the drug’s favorable safety profile counted for very little in the panel discussion. A hard lesson to be learned for others in the business.